3-oxime and 3-aza steroids



3,541,117 3-0XIME AND 3-AZA STEROIDS Arvin Pranlal Shrolf, Piscataway, N.J., assignor to Ortho Pharmaceutical Corporation, a corporation of New Jersey No Drawing. Division of application Ser. No. 592,295,

Nov. 7, 1966, now Patent No. 3,455,903. Continuationin-part of applications Ser. No. 412,828, Nov. 20, 1964, and Ser. No. 424,184, Jan. 8, 1965. This application Aug. 12, 1968, Ser. No. 772,874

Int. Cl. C07c 169/20 US. Cl. 260397.4 12 Claims ABSTRACT OF THE DISCLOSURE Compounds having the formula wherein R is hydrogen, lower alkyl of 1 to 4 carbon atoms, chlorine, bromine 'or fluorine. R is hydrogen or alkyl from 1 to 11 carbon atoms and R is hydrogen or lower acyl of up to 10 carbon atoms which are progestational agents and, in particular possess anti-ovulatory activity.

United States Patent 3,541,117 Patented Nov. 17, 1970 and wherein R is hydrogen, lower alkyl of 1 to 4 carbon atoms, chlorine, bromine or fluorine, R is hydrogen or alkyl from 1 to 11 carbon atoms, and R" is hydrogen or lower acyl of up to 10 carbon atoms.

The 3-oximes, acylated 3-oximes and 3-aza compounds of the present invention have activity as progestational agents, and more particularly, possess anti-ovulatory activity.

Steroidal oximes can conventionally be prepared by re action of a carbonyl group on the steroid with a hydroxylamine salt in the presence of a base such as pyridine, sodium hydroxide or sodium acetate.

When a steroid having a carbonyl group at the 3- and 20-positions is subjected to treatment with a hydroxylamine salt under basic conditions, the dioxime would be the expected product. Due to the presence of a 17-ester group in the starting compounds from which the oximes of this invention are prepared, steric hindrance prevents the oxirnation of the ZO-carbonyl. The 17-ester can be readily converted to the alcohol by hydrolysis.

The oxime is subjected to Beckrnann rearrangement in the presence of an acidic reagent to form the corresponding 3-aza-A-homo steroid. Typical acidic reagents which may be used are thionyl chloride, polyphosphoric acid, p-toluenesulfonyl chloride, p-acetylaminobenzene-sulfonyl chloride, p-aminobenzenesulfonyl chloride and phosphorus pentachloride.

The oxime at the 3-position is esterified by treating the starting material with an organic acid chloride or acid anhydride such as acetyl chloride, acetic anhydride, propionyl chloride, propionoic anhydride, n-butyryl chloride, n-butyric anhydride, isobutyryl chloride, isobutyric anhydride, capryl chloride, caproic anhydride, pelargonyl chloride, pelargonic anhydride, benzoyl chloride, benzoic anhydride, etc.

As starting materials for the preparation of the oximes, there are used compounds of the structural formula:

wherein R is hydrogen, lower alkyl of l to 4 carbon atoms, chlorine, bromine or fluorine, and R' is alkyl from 1 to 11 carbon atoms.

The following examples illustrate the invention:

EXAMPLE I 17a-acetoxy-pregn-4-en-3,20-dion-3-oxime 17a-propionoxy-pregn-4-en-3,20-dion-3-oxime Following the procedure of Example I, 17u-propionoxy progesterone yielded 17oz propionoxy-pregn-4-en-3,20- dion-3-oxime having a melting point of 205-209 C.

Calculated for C H NO .Theory (percent): C, 71.79; H, 8.79; N, 3.49. Found (percent): C, 71.72; H, 8.73; N, 3.65.

EXAMPLE III 17a-caproxy-pregn-en-3,20'dion-3-oxime Following the procedure of Example I, 17u-caproxy progesterone yielded 17a-caproxy-pregn-4-en-3,20-dion-3- oxime having a melting point of 189-192 C.

Calculated for C H NO .Theory (percent): C, 73.10; H, 9.32; N, 3.16. Found (percent): C, 73.18; H, 9.61; N, 3.25.

EXAMPLE IV 6a-methyl-17a-acetoxy-pregn-4-en-3,20-dion-3-oxime Following the procedure of Example I, 6a-methyl-17aacetoxy progesterone yields 6a-methy1-17a-acetoxy-pregn- 4-en-3,20-dion-3-oxime having a melting point of 215- 218 C.

Calculated for C H NO .-Theory (percent): C, 71.79; H, 8.79; N, 3.49. Found (percent): C, 71.78; N, 8.91; N, 3.61.

EXAMPLE V 6a-methyl-17u-pr0pionoxy-pregn-4-en-3,20-dion-3-oxime Following the procedure of Example I, 6a-methyl-l7otpropionoxy progesterone yields 60t-II1CIhYl-l7tX-P1'OPIOI1- oxy-pregn-4-en-3,20-dion-3-oxime having a melting point of 122-124 C.

Calculated for C H NO .Theory (percent): C, 72.25; H, 8.98; N, 3.37. Found (percent): C, 72.43; H, 9.13; N, 3.49.

EXAMPLE VI 6a-methyl-l7a-caproxy-pregn-4-en-3,20-dion-3-0xime Following the procedure of Example I, 6a-methyl-17acaproxy progesterone yields 6a-methyl-17a-caproxy-pregn- 4-en-3,20-dion-3-oxime having a melting point of 97- 98 C.

Calculated for C H NO .Theory (percent): C, 73.48; H, 9.47; N, 3.06. Found (percent): C, 72.98; H, 9.56; N, 3.55.

Utilizing the method of Example I, the following related compounds are prepared starting from the appropriate progesterone:

17a-undecyloxy-pregn-4-en-3,20-dion-3-oxime, 6a-methyl-17a-undecyloxy-pregn-4-en-3,20-dion-3- oxime, 6a-ethyl-17a-acetoxy-pregn-4-en-3,20-dion-3-oxime, 6a-propyl-17a-acetoxy-pregn-4-en-3,20-dion-3-0xime, 6u-chloro-17a-propionoxy-pregn-4-en-3,20-dion-3- oxime, 6a-bromo-17a-caproxy-pregn-4-en-3,20-dion-3-oxime, 6ot-fiuoro-17a-acetoxy-pregn-4-en-3,20-dion-3-oxime.

4 EXAMPLE v11 3-aza- 1 7a-acetoxy-A-homo-4a-pregnen-4,20-dione 4.0 grams of 17a-acetoxy-pregn-4-en-3,20-dion-3-oxime was dissolved in 30 ml. of dioxane and treated with 5.0 ml. of thionyl chloride. The brown solution was stirred at room temperature for one and one-half hours. The reaction mixture was poured into an excess of ice water and extracted with methylene chloride. The methylene chloride layer was washed with sodium bicarbonate solution until neutral. The organic layer was again washed with water and dried over sodium sulfate. On evaporation, it gave a brown oil which was recrystallized from acetonehexane. The crystals were washed with cold ether to yield 1.4 grams of 3-aza-17a-acetoxy-A-homo-4a-pregnen-4,20- dione having a melting point of 274-277 C.

Calculated for C H NO .Theory (percent): C, 71.29; H, 8.58; N, 3.61. Found (percent): C, 71.53; H, 8.61; N, 3.80.

EXAMPLE VIII 3-aza-6a-methyl-17a-acetoxy-A-homo-4a-pregnen- 4,20-dione Following the procedure of Example VII, 6a-methyl- 17a-acetoxy-pregn-4-en-3,20-dion-3-0xime yields 3-aza-6amethyl-17a-acetoxy-A-homo-4a-pregnen-4,20-dione having a melting point of 184-186 C.

Calculated for C H NO .-Theory (percent): C, 71.79; H, 8.79; N, 3.49. Found (percent): C, 71.18; H, 8.77; N, 3.59.

Utilizing the method of Example VII, the following related compounds are prepared starting from the appropriate 3-oxime.

3-azal 7a-pr0pionoxy-A-homo-4a-pregnen-4,20-dione,

3-aza-1 7 a-caproxy-A-homo-4a-pregnen-4,20-dione,

3-aza-17a-undecyloxy-A-homo-4a-pregnen-4,20-dione,

3-aza-6a-methyl-17a-propionoxy-A-horno-4a-pregnen- 4,20-dione,

3 -aza-6a-methyl- 1 7tx-caproxy-A-homo-4a-p re gnen- 4,20-dione,

3-aza-6tx-ethyl-17a-acetoxy-A-homo-4a-pregnen- 4,20-dione,

3 -aza-6a-propyl-17a-acetoxy-A-homo-4a-pregnen- 4,20-dione,

3-aza-6a-chloro-17a-propionoxy-A-homo-4a-pregnen- 4,20-dione,

3 -aza-6u-fiuoro-17a-acetoxy-A-homo-4a-pregnen- 4,20-dione,

3-aza-6u-bromo-17a-caproxy-A-homo-4a-pregnen- 4,20-dione,

3 -aza-6a-methyl-17tx-undecyloxy-A-homo-4a-pregnen- 4,20-dione.

EXAMPLE IX 3,17a-diacetoxy-6a-methyl-pregn-4-en-3,20-dion-3-oxime 500 mg. of 17a acetoxy-6a-methyl-pregn-4-en-3,20- dion-3-oxime is treated with 1.5 ml. of acetic anhydride and 0.7 ml. of pyridine. The mixture is stirred for ten minutes and poured over ice water. Crude crystals are formed which are collected by filtration and recrystallized from aqueous methanol to yield 485 mg. (88%) of 3,170:- diacetoxy-6a-methyl-pregn-4en-3,20-dion-3-oxime having a melting point of 104-107 C.

Calculated for C H NO .Theory (percent): C, 70.40; H, 8.41; N, 3.16. Found (percent): C, 69.83; H, 8.87; N, 3.21.

EXAMPLE X 3-propi0uoxy-17a-acetoxy-6a-methyl-pregn-4-en- 3,20-dion-3-oxime 1.0 gram of 17a-acetoxy-6a-methyl-pregn-4-en-20-one- 3-oxime is treated with 1.5 ml. of pyridine and 3.0 ml. of propionic anhydride. The mixture is stirred for 15 minutes at room temperature and is added to ice water. The mixture is neutralized with ammonium hydroxide and filtered.

The precipitates are recrystallized from methanol-water to yield 1.2 grams (96.5%) of 3-propionoxy-l7a-acetoxy- 6a-methyl-pregn-4-en-20 -one-3-oxime having a melting point of 81-85 C.

Calculated for C H NO .Theory (percent): C, 70.86; H, 8.59; N, 3.06. Found (percent): C, 70.58; H, 8.73; N, 3.14.

EXAMPLE XI 3-caproxy-17a-acetoxy-6a-methyl-pregn- 4-en-3,20-dion-3-oxime Following the procedure of Example X, and using caproic anhydride as the sterifying agent, there is yielded 1.4 gram (97%) of 3-caproxy-17a-acetoxy-6a-methylpregn-4-en-20-one-3-oxime having a melting point of 105- 108 C.

Calculated for C H NO .Theory (percent): C, 72.11; H, 9.98; N, 2.80. Found (percent): C, 71.92; H, 9.17; N, 2.96.

EXAMPLE XII 3-benzoyloxy-17a-acetoxy-6a-methyl-pregn- 4-en-3,20-dion-3-oxime 3,17a-diacetoxy-6u-ethyl-pregn-4-en-3,20-dion-3-oxime,

3,170; diacetoxy 60: fluoro pregn 4-en-3,20-dion-3- oxime,

3 propionoxy 17oz acetoxy-6u-fluoro-pregn-4-en-3,20-

dion-3-oxime,

3 caproxy 17a propionoxy 6a bromo-pregn-4-en- 3,20-dion-3-oxime,

3 decyloxy 17a propionoxy 61x methyl pregn 4- en-3,20-dion-3-oxime.

What is claimed is: 1. A compound of the formula wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, chlorine, bromine and fluorine, R is selected from the group consisting of hydrogen and alkyl or 1 to 11 carbon atoms, and R" is selected from the group consisting of hydrogen and 'lower acyl of up to 10 carbon atoms.

2. l7u-acetoxy-pregn-4-en-3,20-dion-3-oxime according to claim 1.

3. 17oz propionoxy pregn 4 en 3,20 3 oxime according to claim 1.

4. 17a caproxy pregn 4 en 3,20 dion 3- oxime according to claim 1.

5. 6a methyl 17a actoxy pregn 4 en 3,20- dion-3-oxime according to claim 1.

6. 6a methyl 17oz propionoxy pregn 4 en- 3,20-dion-3-oxime according to claim 1.

7. 6oz methyl 17a caproxy pregn 4 en 3,20- dion-3-oxime according to claim 1.

8. 3,1701 diacetoxy 6a methyl pregn 4 en- 3,20-dion-3-oxime according to claim 1.

9. 3 propionoxy 17oz acetoxy c methyl pregn- 4-en-3,20-dion-3-oxime according to claim 1.

10. 3 caproxy 17oz acetoxy 6oz methyl pregn- 4-en-3,20-dion-3-oxime according to claim 1.

11. 3 benzoyloxy 17a acetoxy 6oz methyl pregn- 4-en-3,20-dion-3-oxime according to claim 1.

12. A method of preparing compounds of the formula formula COR/I wherein R has the above meaning, and R" is selected from the group consisting of alkyl of from 1 to 11 carbon atoms with a hydroxylamine salt in the presence of a base, and, if desired, hydrolyzing the resultant product.

No references cited.

ELBERT L. ROBERTS, Primary Examiner 33 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION November 17, 1970 Patent No. s a Dated Arvin Pranlal Shroff Inventor(s) It: is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In Column 3, line &2, "N" should read-H--. In Column 5, line 18, "9.98" should read--9.08--. In Claim 3, line 1, insert --dion-- after "3,20".

(SEAL) Attest:

Ed a M. Fletcher,

WILLIAM E- SGHUYLE, JR. Attesung ()ffim Commissioner of Patents 

